Bone fragility fracture is a major health care concern for our rapidly aging society due to its elevated risk of long-term disability and even premature death and is always associated with ultrastructural changes in bone. In the hierarchy of bone, lamellae, as the basic building unit of human bone, are a sheet-like biocomposite consisting of mineralized collagen fibrils, an extrafibrillar matrix comprised of mineral crystals and non-collagenous proteins (NCPs), and water filling the interstitial spaces. Although the mechanical behavior of mineralized collagen fibrils have been extensively studied, the contribution of the extrafibrillar matrix to the mechanical behavior of bone is still poorly understood. Previous evidence shows that NCPs may not only regulate bone metabolisms but also play a significant role in the ultrastructural integrity of bone. In this study, we propose a mechanistic model of the extrafibrillar matrix in bone that the mineral crystals in the matrix are bounded through a thin organic interface of NCPs. The overall hypothesis is that non-collagenous proteins (NCPs) play a critical role in bone nanomechanics by facilitating the interfacial sliding between the HA polycrystals in the extrafibrillar matrix of bone. To test the hypothesis, both numerical simulations and experimental verifications will be implemented to address the two specific aims. Aim 1: To determine the effect of the organic interface between HA polycrystals on the mechanical behavior of the extrafibrillar matrix in bone using a finite element approach with a novel interface zone model: In Aim 1, a novel interface zone model will be used in the finite element simulation of the extrafibrillar, in which hydroxyapatite (HA) polycrystals are bounded through an organic interface, which is comprised of NCPs and water molecules and allows for sliding and separation between the mineral crystals. It is anticipated that the plastic deformation is realized through the sliding between HA crystals along the organic interface. In addition, the effect of crystal size and shape and orientation distribution on the mechanical behavior of the extrafibrillar matrix will be scrutinized in this study. Aim 2 To experimentally verify the novel mechanistic model using an in vitro experimental model: In Aim 2, we hypothesize that the organic interface between the mineral crystals in the extrafibrillar matrix will be compromised if the structure of proteoglycans is altered by removing polysaccharides, which are the major components of proteoglycans that help anchor the GAGs onto the core proteins. The interruption of PGs will result in a defected interface zone between the mineral crystals, thus leading to weakening of the lamellae. To test the hypothesis, we propose to use a novel nanoscratch test technique [81] to measure the in situ mechanical properties of individual lamellae with and without impairment of proteoglycans. The novel mechanistic model proposed in this study, if proved, will open a new avenue for studying the structural role of NCPs in bone fragility. The potential impact of such understanding is multifaceted. First, it will significantly improve the multiscale modeling of bone tissues. Second, this concept can be extended to elucidate the involvement of NCPs in age- and disease related bone fragility fractures. Finally, NCPs may be used as biomarkers in clinical settings to assess the risk of bone fragility fractures.